Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 132 (2014) 465–476

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Molecular structure investigation of organic cocrystals of 1,10-phenanthroline-5,6-dione with aryloxyacetic acid: A combined experimental and theoretical study G.S. Suresh Kumar a,⇑, A. Antony Muthu Prabhu b, N. Bhuvanesh c, X.A.V. Ronica b, S. Kumaresan d a

Faculty of Chemistry, Department of Science and Humanities, Dr. Mahalingam College of Engineering and Technology (Dr. MCET), Udumalai Road, Pollachi 642 003, Tamil Nadu, India Department of Chemistry, Manonmaniam Sundaranar University, Tirunelveli 627 012, Tamil Nadu, India Department of Chemistry, Texas A & M University, College Station, TX 77842, USA d Department of Chemistry, Noorul Islam University, Kumaracoil, Thuckalay 629 180, Tamil Nadu, India b c

h i g h l i g h t s

g r a p h i c a l a b s t r a c t

 Cocrystals were synthesized via

solvent mediated crystallization and neat grinding methods.  Cocrystal 1 is stabilized through H-bonding as well as p–p interaction.  Cocrystals 1 and 2 are stable up to 210 °C.  Binding energy of cocrystal 2 is higher than that of cocrystal 1.  Formation of H-bonding in cocrystals 1 and 2 is confirmed by MEP and NBO analysis.

a r t i c l e

i n f o

Article history: Received 20 February 2014 Received in revised form 30 April 2014 Accepted 9 May 2014 Available online 17 May 2014 Keywords: 1,10-Phenanthroline-5,6-dione 2-Naphthoxyacetic acid 2-Formylphenoxyacetic acid DFT MEP NBO

a b s t r a c t Two organic cocrystals namely, 1,10-phenanthroline-5,6-dione:2-naphthoxyacetic acid [(phendione) (2-naa)] (1) and 1,10-phenanthroline-5,6-dione:2-formylphenoxyacetic acid [(phendione)(2-fpaa)] (2) were synthesized and studied by single crystal XRD, FT-IR, NMR, thermogravimetric, and powder X-ray diffraction analysis. The molecular properties of cocrystals were studied using density functional theory (DFT), basis set B3LYP/6-31G(d,p). Both cocrystals are stabilized through intermolecular hydrogen bonding (OAH  N). The total electron density and molecular electrostatic potential surfaces of the cocrystals were constructed by NBO analysis using B3LYP/6-31G(d,p) method to display the electrostatic potential (electron + nuclei) distribution. The energy gap between HOMO and LUMO was measured for both cocrystals. Ó 2014 Elsevier B.V. All rights reserved.

Introduction Cocrystal technology has shown great promise in rectifying the undesirable properties of a drug substance. A pharmaceutical ⇑ Corresponding author. Tel.: +91 9003180667. E-mail address: [email protected] (G.S. Suresh Kumar). http://dx.doi.org/10.1016/j.saa.2014.05.020 1386-1425/Ó 2014 Elsevier B.V. All rights reserved.

cocrystal is a single crystalline solid that incorporates two neutral molecules, one being an active pharmaceutical ingredient (API) and the other a cocrystal former [1]. Once an API has been selected for cocrystallization studies, non-toxic cocrystallizing agent should be chosen so as to result in a pharmaceutically acceptable product. In recent times, cocrystal formation using the crystal engineering approach has been shown to be effective for altering the

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physicochemical properties such as melting point [2], solubility [3], thermal [4], and photostability [5] as well as mechanical properties [6] of active pharmaceutical ingredients (APIs). The recent progress in density functional theory (DFT) has provided a very useful tool for understanding molecular properties and for explaining the behavior of atoms in molecules. DFT methods have become very popular in the past decade due to their accuracy and less computational time [7]. The calculation of a wide range of molecular properties with DFT allows a close connection between theory and experiment, and often leads to important clues about the geometric, electronic, and spectroscopic properties of the systems being studied [7]. 1,10-Phenanthroline-5,6-dione (phendione), displays significant anticancer activity, both with and without a coordinated metal [8]. It is also an excellent anti-Candida agent [9]. Phenoxyacetic acid moiety is associated with potent antimicrobial, antidiabetic, antibiotic, anti-obesity, antiplatelet aggregation activities, etc. [10a,b]. In continuation of our work in organic cocrystals [10], herein we report the syntheses of binary cocrystals of 1,10-phenanthroline5,6-dione (phendione) with 2-naphthoxyacetic acid (2-naa) and 2-formylphenoxyacetic acid (2-fpaa) through solvent mediated crystallization as well as neat grinding methods (Scheme 1). The structure of the newly synthesized cocrystals were analyzed using FT-IR spectroscopy, powder X-ray diffraction (PXRD), NMR, and single crystal X-ray diffraction (SXRD). The molecular properties of the cocrystals [(phendione)(2-naa)] (1) and [(phendione) (2-fpaa)] (2) were studied using DFT method.

Experimental General details 1,10-Phenanthroline-5,6-dione (phendione) [11], 2-naphthoxyacetic acid (2-naa) and 2-formylphenoxyacetic acid (2-fpaa) [12] were synthesized as per the literature methods. FT-IR spectra were recorded on a JASCO FT-IR-410 spectrometer in the range 4000– 400 cm1 on KBr discs. The 1H NMR and 13C NMR spectra were recorded on a Bruker (Avance) 400 MHz NMR instrument using TMS as internal standard and DMSO-d6 as solvent. Thermogravimetric analysis (TGA) experiments were performed on a Diamond Thermal Analyzer in the temperature range of 25–700 °C under nitrogen atmosphere at a heating rate of 10 °C/min. Powder X-ray diffraction data were collected using a XPERT-PRO diffractometer system with Cu Ka1, Cu Ka2, and Cu Kb with radiation of

wavelength 1.54060, 1.54443, and 1.39225 Å respectively. Powder X-ray diffraction data were recorded in the range 10° 6 2h 6 80°. The step size was 0.0170°. Elemental analyses were performed on a Perkin Elmer 2400 Series II Elemental CHNS analyzer.

Syntheses of cocrystals [(phendione)(2-naa)] (1) and [(phendione) (2-fpaa)] (2) via solution crystallization method 1,10-Phenanthroline-5,6-dione (1.0 mmol) and 2-naphthoxyacetic acid (1.0 mmol) or 2-formylphenoxyacetic acid (1.0 mmol) were dissolved individually in aqueous ethanol (1:1 v/v, 10 mL) in two Erelenmeyer flasks (25 mL) at room temperature. The mixtures were stirred and warmed until the starting materials completely dissolved. These mixtures were filtered to avoid the inclusion of any undissolved starting materials. Slow evaporation of the filtrate under ambient conditions over 3–4 days yielded crystals of [(phendione)(2-naa)] (1) (yield: 80%) and [(phendione)(2-fpaa)] (2) (yield: 84%) suitable for X-ray diffraction. Anal. Calcd. for [(phendione)(2-naa)] (1) C24H16N2O5: C, 69.90; H, 3.91; N, 6.79%. Found: C, 69.84; H, 3.98; N, 6.72% and for [(phendione)(2-fpaa)] (2) C21H14N2O6: C, 64.62; H, 3.62; N, 7.18%. Found: C, 64.60; H, 3.66; N, 7.10%.

Solvent-free syntheses of [(phendione)(2-naa)] (1) and [(phendione)(2-fpaa)] (2) via neat grinding method 1,10-Phenanthroline-5,6-dione (1.0 mmol) and 2-naphthoxyacetic acid (1.0 mmol) or 2-formylphenoxyacetic acid (1.0 mmol) were ground well individually at 30 °C under dry condition. After 30 min, red/brown colored solids of [(phendione)(2-naa)] (1) and [(phendione)(2-fpaa)] (2) were found to have formed (PXRD, Figs. s1 and s2, vide Supporting information).

X-ray structure determination A BRUKER APEX 2 X-ray (three-circle) diffractometer was employed for crystal screening, unit cell determination, and data collection. Integrated intensity information for each reflection was obtained by reduction of the data frames with the program APEX2 [13]. A solution was obtained readily using SHELXTL (XS) [14]. Absence of additional symmetry and subcell were verified using PLATON [15] and CELL_NOW respectively. Olex2 was employed for the final data presentation and structure plots [16].

Scheme 1. Syntheses of cocrystals 1 and 2.

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Computational methodology Theoretical studies on cocrystals 1 and 2 in gas phase were performed using the analytical gradient methods of DFT with Becke’s three parameters (B3) exchange functional together with the Lee–Yang–Parr (LYP) non-local correlation functional, symbolized B3LYP [17] by means of 6-31G(d,p) basis set implemented in Gaussian 09 software package [18]. The optimized structural parameters in gas phase were used to calculate energies and thermodynamic properties of the compounds. The energies of the highest occupied (HOMO) and lowest unoccupied (LUMO) molecular orbital, and HOMO–LUMO energy gap have also been measured. Gauss-View 5.0.8 visualization program [19] was used to construct the molecular electrostatic potential (MEP) map and the shape of the frontier molecular orbitals. The natural charges of the atoms are determined by natural bond orbital (NBO) analysis using B3LYP/6-31G(d,p) method. Isoelectronic molecular electrostatic potential surfaces (MEP) and electron density surfaces [20] mapped with electrostatic potential were calculated. Results and discussion

Table 1 Crystal data and structure refinement parameters of cocrystals 1 and 2. Cocrystal 1

Cocrystal 2

CCDC no. Empirical formula Formula weight Appearance Crystal size Wavelength (Å) Crystal system Space group Unit cell dimensions

899820 C24H16N2O5 412.39 Red block 0.19  0.06  0.06 0.71073 Å Monoclinic Cc a = 7.107(3) Å b = 17.121(8) Å c = 30.825(13) Å a = c = 90° b = 96.412(4)°

Volume Z Density (calculated) Absorption coefficient F(0 0 0) Theta range for data collection Index ranges

3727(3) Å3 8 1.470 mg/m3 0.105 mm1 1712 2.38–27.50° 9 6 h 6 9, 22 6 k 6 22, 40 6 l 6 39 21,146 8339 [R(int) = 0.0215] 99.3% Semi-empirical from equivalents 0.9937 and 0.9804 Full-matrix leastsquares on F2 8339/2/561 1.030 R1 = 0.0334, wR2 = 0.0825 R1 = 0.0367, wR2 = 0.0850 0.232 and 0.170 e Å3

899821 C21H14N2O6 390.34 Brown block 0.40  0.40  0.08 0.71073 Å Triclinic P–1 a = 7.7654(3) Å b = 9.558(4) Å c = 12.757(5) Å a = 84.072(4)° b = 85.611(4)° c = 71.416(4)° 878.9(6) Å3 2 1.475 mg/m3 0.110 mm1 404 1.61–27.50° 9 6 h 6 9, 12 6 k 6 12, 16 6 l 6 16 10,187 3954 [R(int) = 0.0223]

Crystal structure The crystallographic data and structure refinement parameters of the cocrystals 1 and 2 are presented in Table 1. The bond lengths and angles are given in Table 2. The hydrogen bond geometry is shown in Table 3. Crystallographic data for the cocrystals 1 and 2 have been deposited with the Cambridge Crystallographic Data Centre (CCDC) (deposition numbers: 899820 and 899821 respectively). Single crystal XRD of cocrystal 1

Reflections collected Independent reflections Completeness to theta Absorption correction Max. and min. transmission Refinement method Data/restraints/parameters Goodness-of-fit on F2 Final R indices [I > 2sigma(I)] R indices (all data)

Fig. 1 shows the ORTEP diagram of cocrystal 1 along with the adopted atomic numbering scheme. The asymmetric unit of cocrystal 1 contains two molecules of 1,10-phenanthroline-5,6dione (phendione) and two molecules of 2-naphthoxyacetic acid (2-naa). The compound crystallizes in noncentrosymmetric space group Cc, with Z = 8 (Z0 = 2). Absence of additional symmetry and smaller unit cell were verified using Platon and CELL_NOW respectively. The crystal structure shows that there is no proton transfer from the carboxyl group of 2-naa to phendione in the asymmetric unit. A predicted intermolecular hydrogen bonding motif O5AH5  N2 is observed between the carboxylic OAH of 2-naa and the nitrogen of phendione. From Table 2, the CAO bond lengths [C24AO4: 1.197(2), C24AO5: 1.328(2)] indicate that the acid moiety is present as ACOOH. Each 2-naa combines with one unit of phendione through O5AH5  N2 (O5AH5  N2 distance is 2.834 Å) hydrogen bonding with Etter’s [21] graph set designator D forming discrete molecules. O5AH5  N2 is essentially linear, with an angle 173.08° (Table 3). The dihedral angle between the carboxyl group (O4AC24AO5) of 2-naa and the pyridyl ring of phendione is 20.84°. Phendione lies almost on the same plane of the naphthalene ring of 2-naa, since its dihedral angle is 5.55°. Two types of p–p stacking forces were observed (Fig. 2) between non-hydrogen bonded pyridyl ring of phendione and substituted phenyl ring of 2-naa (3.524 and 3.584 Å). Fig. 3 depicts the crystal packing arrangement of cocrystal 1 along b-axis.

Largest diff. peak and hole

97.9% Semi-empirical from equivalents 0.9912 and 0.9572 Full-matrix leastsquares on F2 3954/0/263 1.068 R1 = 0.0377, wR2 = 0.0970 R1 = 0.0444, wR2 = 0.1018 0.308 and 0.199 e Å3

(phendione) and one molecule of 2-fpaa. The compound crystallizes in noncentrosymmetric space group P  1 with Z = 2. In the asymmetric unit, the crystal structure shows that there is no proton transfer from the carboxyl group of 2-fpaa to the phendione. From the CAO bond lengths [C8AO3: 1.2115(16) Å, C8AO2: 1.3177(15) Å] of the carboxyl acid moiety (Table 2), the nondeprotonation of the ACOOH group could be inferred. Each 2-fpaa (carbonyl OAH) combines with one unit of phendione (pyridyl N-atom) through O2AH2  N2 (O2AH2  N2 bond distance is 2.783 Å) hydrogen bonding with Etter’s [21] graph set designator D forming discrete molecules. The N2  H5 bond length of cocrystal 1 (1.999 and 1.981 Å) is longer than the N2  H2 bond length of cocrystal 2 (1.957 Å) (Table 3). This reveals that hydrogen bond of cocrystal 2 is stronger than cocrystal 1 and this gives extra stability to cocrystal 2. The dihedral angle between the carboxyl group (O3AC8AO2) of 2-fpaa and the phendione (hydrogen bonded pyridyl ring) is 38.07°, and that of phendione (hydrogen bonded pyridyl ring) and aryl ring of 2-fpaa is 63.17°. Extra stabilization through p–p interactions could not be visualized as the short contacts are more than 4.1 Å. Fig. 5 shows the crystal packing arrangement along a⁄ axis.

Single crystal XRD of cocrystal 2 FT-IR spectra of cocrystals 1 and 2 The ORTEP diagram of the cocrystal 2 is shown in Fig. 4. The geometrical parameters of 2 are listed in Table 2. The asymmetric unit of 2 contains one molecule of 1,10-phenanthroline-5,6-dione

The formation of a cocrystal could be confirmed by the changes in the carbonyl frequencies in the crystals. The change in carbonyl

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Table 2 Selected bond lengths and bond angles of experimental and theoretical studies on cocrystals 1 and 2. Bond

Cocrystal 1

Bond

SCXRD

PM3

HF

DFT

Bond lengths (Å) C13AO3 C24AO4 C24AO5 O5AH5 C10AN2 C5AN2 C9AN2 C4AN2

1.378 1.197 1.328 0.840 1.342 1.345 1.333 1.347

1.379 1.220 1.337 0.974 1.354 1.361 1.350 1.357

1.349 1.187 1.313 0.961 1.316 1.320 1.319 1.323

1.365 1.214 1.330 0.999 1.333 1.339 1.343 1.339

Bond angles (°) C13AO3AO23 C23AC24AO4 O4AC24AO5 C24AO5AH5 C6AC1AC2 C3AC2AC1

115.36 125.40 125.78 109.50 118.72 117.22

116.70 126.35 118.71 113.05 114.19 113.96

119.47 125.15 125.43 112.40 117.50 117.58

118.02 124.47 126.26 111.39 117.47 117.64

(19) (2) (2) (2) (2) (2) (12) (15) (15) (14) (15)

Table 3 Hydrogen bond geometries (Å and °) in the crystal structure of 1 and 2. d(H  A)

d(DAH)

d(DAH  A)

DAH  A

Cocrystal 1 O5AH5  N2 O5aAH5a  N2a

1.999 1.981

0.840 0.840

2.834 2.816

172.30 173.08

Cocrystal 2 O2AH2  N2

1.957

0.840

2.783

167.06

A – acceptor, D – donor, and H – hydrogen atom.

frequencies in cocrystals is due to the involvement of carboxyl group in hydrogen bond formation because of the hydrogen bond interactions that disturb the electron distribution on carboxyl group [22]. The IR spectra of phendione, 2-naa, 2-fpaa, and cocrystals (1 and 2) are given in the Supporting information (vide Supporting information, Figs. s3–s7). Table 4 shows the carbonyl stretching frequencies of starting materials and cocrystals (1 and 2). The carbonyl stretching frequency for cocrystals 1 and 2 is above 1600 cm1 in the infrared

Cocrystal 2 SCXRD

PM3

HF

DFT

C1AO1 C8AO3 C8AO2 O2AH2 C21AN2 C18AN2 C10AN1 C14AN1

1.366 1.211 1.318 0.840 1.339 1.341 1.335 1.341

1.385 1.220 1.341 0.975 1350 1.357 1.354 1.362

1.346 1.187 1.310 0.962 1.316 1.320 1.319 1.323

1.360 1.214 1.328 1.001 1.334 1.339 1.339 1.344

C1AO1AC7 C7AC8AO3 O3AC8AO2 C8AO2AH2 C17AC16AC15 C13AC15AC16

117.66 124.47 125.27 109.50 118.02 117.40

117.11 128.52 118.16 113.02 113.93 114.18

120.82 124.73 125.76 112.59 117.49 117.59

119.48 123.97 126.57 111.48 117.47 117.64

(15) (16) (15) (17) (16) (17) (16) (9) (11) (12) (11) (11)

spectra confirming the presence of nonionized carboxylic acids [22]. Two intense carbonyl bands at 1755 and 1685 cm1 are displayed in the IR spectrum of cocrystal 1. The band at 1755 cm1 is due to the carbonyl stretching frequency of 2-naa and 1685 cm1 is due to the carbonyl stretching frequency of the phendione in the cocrystal 1. In the IR spectrum of cocrystal 2, two bands at 1724 and 1693 cm1 are due to the carbonyl stretching frequencies of 2-fpaa and 1682 cm1 is due to the carbonyl stretching frequency of phendione. Carbonyl stretching frequencies of phendione is not much affected in cocrystals 1 and 2 which confirm the noninvolvement of phendione carbonyl in hydrogen bonding. The change in carbonyl frequency (COOH) in cocrystals (1 and 2) is due to the involvement of carboxyl group in hydrogen bond formation. From single crystal XRD data, the carbonyl (C@O) bond length of cocrystal 1 (1.197 Å) is lower than 2-naa (1.212 Å) [22e–f]. The decrease in bond length of carboxyl group decreases the carbonyl stretching frequency of cocrystal 1. But in cocrystal 2 (1.211 Å), the carbonyl bond length is higher than that of 2-fpaa (1.203 Å) [22g]. The increase in bond length of carboxyl group increases the carbonyl stretching frequency of cocrystal 2.

Fig. 1. ORTEP diagram of [(phendione)(2-naa)] (1) along with the adopted atomic numbering scheme.

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Fig. 2. H-bonding and p–p stacking interactions in [(phendione)(2-naa)] (1).

Fig. 3. Packing arrangement of [(phendione)(2-naa)] (1) along b axis.

Fig. 4. ORTEP diagram of [(phendione)(2-fpaa)] (2) along with the adopted atomic numbering scheme.

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consistent with the elimination of one molecule of naphthol moiety. At higher temperatures, the weight loss is experienced at about 325 °C. The loss in mass at this point is about 14.55% (calculated: 13.90%) and may be attributed to the loss of one molecule of acetic acid. At still higher temperatures, the decomposition speeds up again and at about 380 °C, a weight loss of 50.92% (calculated: 50.60%) is observed, which may be due to the decomposition of the remaining phendione moiety (vide Supporting information, Fig. s12). Cocrystal 2 is stable up to 210 °C at which point it loses about 41.02% (calculated: 40.5%) of its weight. This may be due to the elimination of one molecule of formaldehyde, one molecule of carbon dioxide, one molecule of methanol, and two molecules of carbon monoxide. At 270 °C, there is a weight loss of about 20% (calculated: 20.5%) which may be attributed to the loss of one molecule of phenyl unit. Further increase in temperature speeds up the decomposition and at about 370 °C, a weight loss of 38.97% (calculated: 39%) was noticed which may be due to the decomposition of the remaining phendione moiety (vide Supporting information, Fig. s13). Powder XRD of cocrystals 1 and 2

Fig. 5. Packing arrangement of [(phendione)(2-fpaa)] (2) along a⁄ axis.

Table 4 Carbonyl stretching frequencies mC@O (cm1) of starting materials and cocrystals 1 and 2. Compounds

Stretching frequencies mC@O (cm1)

Phendione 2-naa 2-fpaa

1686 1738 1760 (COOH) 1720 (CHO) 1755 1685 1724 1693 1682

Cocrystal 1 Cocrystal 2

1

H NMR and

13

C NMR spectra of cocrystals 1 and 2

Liquid 1H NMR spectra of cocrystals are used to find out the stoichiometric ratio of individual molecules in cocrytal [10a,10b]. 1 H NMR (in DMSO-d6) spectra of cocrystals 1 and 2 confirm that the 1:1 stoichiometric ratio of phendione with 2-naphthoxyacetic acid and 2-formylphenoxyacetic acid (vide Supporting information, 1 H NMR and 13C NMR spectra, Figs. s8–s11 and peak analysis of cocrystals (1 and 2), Table s1 and s2). The chemical shift (d ppm) of AOCH2 protons of cocrystals 1 (H23A and H23B) and 2 (H7A and H7B) are observed at 4.81 and 4.90 ppm whereas AOCH2 carbon of cocrystal 1 (C23) and cocrystal 2 (C7) resonate at 64.5 and 65.1 ppm respectively. 1 H NMR and 13C NMR spectra of cocrystals 1 and 2 show that proton and carbon atoms of phendione have similar chemical shift value in both cocrystals. This indicates that in liquid NMR spectra the cocrystals show the chemical shift of individual molecules.

TGA/DTA of cocrystals 1 and 2 Cocrystal 1 is stable up to 210 °C at which point it quickly suffers about 34.43% weight loss (calculated: 35.50%) which is

Powder XRD is useful for the fast identification of the new phases of compounds. The cocrystal formed between phendione and 2-naa/2-fpaa at a molar ratio of 1:1 is further supported by powder XRD studies. Powder XRD pattern of the 1:1 ground mixture of the starting materials displayed similar pattern of the cocrystals of both 1 and 2 obtained from solution crystallization (vide Supporting information, Figs. s1 and s2). Theoretical studies Gas phase geometry optimizations were performed starting from the crystal structures of cocrystals 1 and 2 at the B3LYP/631G(d,p) level of theory using Gaussian 09W software [18]. In most theoretical studies, optimizing the geometry of the species under investigation is the first step. Gas phase geometrical parameters of the optimized structures of cocrystals 1 and 2 at the PM3, HF/ 3-21G(d), and DFT/6-31G(d,p) levels are listed in Table 2. The conformational analysis based on the geometrical parameters such as bond length, bond angle, and planarity of cocrystals 1 and 2 (Table 2) reveals that DFT method represents a good correlation between the calculated geometrical parameters and the single crystal XRD data. Fig. 6 shows the optimized structures of cocrystals 1 and 2. The calculated geometrical parameter displays good correlation with experimental values that can lead to the calculation of other parameters for the cocrystals 1 and 2. The molecular properties of phendione, 2-naa, 2-fpaa, cocrystal 1, and cocrystal 2 are summarized in Table 5. The total energy of both cocrystals is more negative in magnitude than that of individual molecules. The binding energy of the cocrystals is given as,

DE ¼ Ecocrystal  ðEphendione þ E2-naa or2-fpaa Þ

ð1Þ

where Ecocrystal, Ephendione, and E2-naa or 2-fpaa represent the energy of the cocrystal, phendione, 2-naa, and 2-fpaa respectively. Cocrystal 1 has more negative binding energy than cocrystal 2. The binding energies of cocrystals are negative, indicating that the cocrystals can be formed thermodynamically. Generally, the binding energies of the cocrystals increase with the increase in the number of the weak bonds (H-bonds, van der Waals, etc.) formed [23]. H-bonding, p–p, and CAH  p interactions are confirmed from both the theoretical binding energy and SCXRD studies of cocrystal 1. Theoretically calculated Gibbs free energy changes (DG) using DFT calculations is of a negative magnitude (Table 5) suggesting that the formation of cocrystals was a spontaneous and feasible

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(a) [(phendione)(2-naa)] (1)

(b) [(phendione)(2-fpaa)] (2) Fig. 6. Optimized structures of cocrystals (a) 1 and (b) 2.

process. The higher DS values indicate that the cocrystal 2 has lower degree of randomness than the cocrystal 1 in gas phase. Frontier molecular orbital (FMO) analysis Molecular orbitals (HOMO and LUMO) and their properties are very useful for physicists, chemists, and biochemists; and are very important parameters for quantum chemistry. This is also used by the frontier electron density for predicting the most reactive position in p-electron systems [24]. The conjugated molecules are analyzed by the highest occupied molecular orbital–lowest unoccupied molecular orbital (HOMO–LUMO) separation, which is the result of a significant degree of intramolecular charge transfer from the end-capping electron-donor groups to the efficient electron-acceptor groups through p-conjugated path [25]. Both the highest occupied and lowest unoccupied molecular orbitals are the main factors taking part in chemical stability [26]. HOMO and LUMO energy of cocrystals 1 and 2 and their formers were calculated by B3LYP/6-31G(d,p) method (Table 5). This electronic absorption corresponds to the transition from the ground to the first excited state and is mainly described by one-electron excitation from HOMO to LUMO. The energy of HOMO is directly related to the ionization potential while that of ELUMO is directly related to the electron affinity. The energy gap between HOMO and LUMO is a critical parameter in determining molecular electrical transport properties [27]. The

interaction between the two molecules leads to the extension of the conjugation system and decrease in the energy gaps. The efficient H-bonding causes the flow of electrons from the protondonor to the proton-acceptor, which intensifies the electron density on the proton-acceptor and widens the energy gap of the cocrystals [23]. It is clear from Fig. 7 that while HOMO is localized on the aromatic rings of 2-naa/2-fpaa, LUMO is localized on the whole molecule of phendione (vide Supporting information, HOMO and LUMO diagram for phendione, 2-naa, and 2-fpaa). The HOMO to LUMO transition implies an electron density transfer from the aromatic rings of 2-naa/2-fpaa to the electron deficient phendione. Cocrystals 1 and 2 possess lower ionization potential data than that of the phendione, and thus they are ready to lose electrons. Absolute hardness and softness are important properties to measure the molecular stability and reactivity. A hard molecule has a large energy gap and a soft molecule has a narrow energy gap. Soft molecules are more reactive than hard ones because they could easily offer electrons to an acceptor. For the simplest transfer of electrons, adsorption could occur at the part of the molecule where softness has the highest magnitude and hardness has the lowest [28]. The thermal stabilities of cocrystals 1 and 2 display higher r values than that of the phendione since several intermolecular interactions exist in the two cocrystals. These indicate that cocrystals 1 and 2 are more reactive than phendione and 2-naa/ 2-fpaa (Table 5).

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Table 5 Theoretical studies on cocrystals 1 and 2. Parameters

Phendione

2-naa

2-fpaa

Cocrystal 1

Cocrystal 2

Total energy, E (kcal/mol) Binding energy, DE (kcal/mol) EHOMO (eV) ELUMO (eV) EHOMO–ELUMO (eV) Dipole moment (Debye) Ionization potential, I (eV) Electron affinity, A (eV) Electronegativity, v (eV) Electrochemical potential, l (eV) Absolute hardness, g (eV) Softness, r (eV) Nucleophilicity, x (eV) Enthalpy, H (kcal/mol) DH (kcal/mol) Gibbs free energy, G (kcal/mol) DG (kcal/mol) Entropy, S (cal/mol K) (a) Electronic (b) Translational (c) Rotational (d) Vibrational DS (cal/mol K) Zero-point vibrational energy (kcal/mol) Rotational constant (GHz)

452434.79 – 7.8591 3.5169 4.3422 2.6879 7.8591 3.5169 5.6880 5.6880 2.1711 0.4606 7.4509 452330.12 – 452361.50 – 105.248 0.00 41.930 32.025 31.292 – 97.45065 0.85555 0.53806 0.33032 452337.68 0.00

432352.29 – 7.6517 0.9588 6.6929 2.1316 7.6517 0.9588 4.3052 4.3052 3.3464 0.2988 2.7693 432222.05 – 432255.48 – 112.104 0.00 41.815 32.349 37.940 – 122.31905 1.84669 0.26013 0.22834 432230.31 0.00

407150.88 – 6.8721 1.8546 5.0175 5.8165 6.8721 1.8546 4.3633 4.3633 2.5087 0.3986 3.7945 407044.78 – 407077.47 – 109.536 0.00 41.471 31.661 36.404 – 98.49396 1.36622 0.46322 0.34668 407052.70 0.00

884732.37 54.71 6.4537 3.9329 2.5208 2.5767 6.4537 3.9329 5.1933 5.1933 1.2604 0.7934 10.6991 884495.55 56.62 884550.27 66.71 183.438 0.00 43.939 37.461 102.038 33.914 220.35554 0.38751 0.04281 0.03856 884511.99 0.00

859396.66 189.01 6.3184 3.6331 2.6853 6.0968 6.3184 3.6331 4.9757 4.9757 1.2318 0.8118 10.0493 859183.68 191.22 859236.83 202.14 178.308 0.00 43.776 36.944 97.588 36.476 197.69819 0.39094 0.05609 0.04907 859199.68 0.00

Zero-point energy (kcal/mol) Mullikan charges

ELUMO = -3.9329 eV

ELUMO = -3.6331 eV

EHOMO = -6.4537 eV

EHOMO = - 6.3184 eV

Energy

(a)

(b)

Fig. 7. HOMO and LUMO energy diagrams of cocrystals (a) 1 and (b) 2.

The nucleophilicity measures the electrophilic power of a molecule. It has been reported that the lower the value of x, the lower the capacity of the molecule to donate electrons [28]. Table 5 reveals that the 2-naa and 2-fpaa donate electron to phendione.

The dipole moment in a molecule is mainly used to study the intermolecular interactions involving the non-bonded type dipole–dipole interactions, because higher dipole moment values indicate stronger intermolecular interactions [29]. Cocrystal 2 has

G.S. Suresh Kumar et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 132 (2014) 465–476

473

(a) Cocrystal 1

(b) Cocrystal 2 Fig. 8. Molecular electrostatic potential map of cocrystals (a) 1 and (b) 2.

higher dipole moment than its former-compounds and cocrystal 1 (Table 5). Analysis of molecular electrostatic potential (MEP) Molecular electrostatic potential (MEP) is related to the electronic density and is a very useful descriptor in understanding sites for electrophilic attack and nucleophilic reactions as well as hydrogen bonding interactions. This is correlated with dipole moments, electronegativity, partial charges, and chemical reactivity of the molecules [29,30]. MEP maps allow us to visualize variable charged regions of a molecule. Knowledge of the charge distributions can be used to determine how molecules interact with one another. Different values of the electrostatic potential are represented by different colours: red represents regions of most negative electrostatic potential, blue region represents regions of most positive electrostatic potential, and green represents regions of zero potential. Potential increases in the following order: red < orange < yellow < green < blue [31]. Fig. 8 shows the MEP maps of cocrystals 1 and 2 determined using DFT/B3LYP 6-31G(d,p) method. As can be seen in Fig. 8, the negative (red1) region is localized on the carbonyl-oxygen atom

1 For interpretation of color in ‘Figs. 2 and 8’, the reader is referred to the web version of this article.

and pyridyl nitrogen atom of phendione with a minimum value of 0.06244 and 0.05883 a.u. for cocrystals 1 and 2 respectively. However, maximum positive (blue) region is localized on the carboxylic acid hydrogen atoms, with a maximum value of 0.06244 and 0.05883 a.u. respectively. The proton/electron donating/accepting behaviors are confirmed by the MEP map of their parent compounds (vide Supporting information). Therefore, MEP maps of cocrystals 1 and 2 (Fig. 8) confirm the existence of an intermolecular OAH  N bonding. The pale blue and yellow regions reveal the presence of weak interactions. Hence it can be said these color differences give the information about the region from where the compounds can have p–p and CAH  p intermolecular interactions in the gaseous phase. In cocrystal 1, the pale blue region is located on the aromatic ring of phendione and the yellow region is located on the aromatic ring of 2-naa. The pale blue region is localized on both the aromatic rings of phendione which confirms the formation of two types of p–p interactions in cocrystal 1. This was confirmed from the SCXRD studies (Fig. 2). For cocrystal 1, H-bonding, p–p, and CAH  p interactions were confirmed from both theoretical and SCXRD studies. But in cocrystal 2, the p–p interaction was not observed in SCXRD which is confirmed by theoretical studies. The MEP map of cocrystal 2 shows that the aromatic rings of both phendione and 2-fpaa have the pale blue region. SCXRD data confirmed the formation of CAH  p interactions. H-bonding and CAH  p interactions of cocrystal 2 are confirmed by both theoretical and SCXRD studies.

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Table 6 NBO results showing the formation of Lewis and non-Lewis orbitals of cocrystal 1 and 2. Bond orbital

Occupancy

Cocrystal 1 C1AO1 1.99558 C2AO2

1.99560

C4AN1

1.98303

C5AN2

1.98431

C9AN1

1.98600

C9AN1

1.69995

C10AN2

1.98603

C10AN2

1.71145

C13AO3

1.98999

C23AO3

1.98991

C24AO4

1.99794

C24AO4

1.99237

C24AO5

1.99613

O5AH5

1.98454

Cocrystal 2 C8AO2 1.99606 C8AO3

1.99792

C8AO3

1.99226

C15AO5

1.99560

C15AO5

1.95269

C16AO6

1.99558

C16AO6

1.95281

C14AN1

1.98303

C10AN1

1.98600

C10AN1

1.70077

C18AN2

1.98432

C18AN2

1.70249

C21AN2

1.98605

Atoms

Contribution from parent NBO (%)

Atomic hybrid contributions (%)

C1 O1 C2 O2 C4 N1 C5 N2 C9 N1 C9 N1 C10 N2 C10 N2 C13 O3 C23 O3 C24 O4 C24 O4 C24 O5 O5 H5

34.41 65.59 34.42 65.58 41.76 58.24 41.14 58.86 40.15 59.85 40.41 59.59 39.38 60.62 37.54 62.46 32.39 67.61 32.41 67.59 34.02 65.98 29.78 70.22 32.03 67.90 79.45 20.55

s(31.19) + p2.20(68.70) s(42.44) + p1.35(57.22) s(31.21) + p2.20(68.69) s(42.44) + p1.35(57.22) s(30.98) + p2.23(68.97) s(35.77) + p1.79(64.05) s(30.75) + p2.25(69.20) s(36.46) + p1.74(63.37) s(31.17) + p2.21(68.76) s(35.98) + p1.77(63.84) s(0.00) + p1.00(99.92) s(0.00) + p1.00(99.76) s(30.07) + p2.32(69.86) s(36.24) + p1.76(63.60) s(0.00) + p1.00(99.91) s(0.00) + p1.00(99.79) s(24.77) + p3.03(75.02) s(32.84) + p2.04(67.09) s(21.32) + p3.68(78.43) s(28.90) + p2.46(71.04) s(34.28) + p1.91(65.61) s(41.65) + p1.39(57.97) s(0.00) + p1.00(99.80) s(0.00) + p1.00(99.68) s(29.36) + p2.40(70.39) s(33.99) + p1.94(65.95) s(27.62) + p2.62(72.32) s(99.73) + p0.00(0.27)

C8 O2 C8 O3 C8 O3 C15 O5 C15 O5 C16 O6 C16 O6 C14 N1 C10 N1 C10 N1 C18 N2 C18 N2 C21 N2

32.12 67.88 34.04 65.96 29.83 70.17 34.42 65.58 35.64 64.36 34.42 65.58 35.64 64.36 41.75 58.25 40.14 59.86 40.39 59.61 41.11 58.89 39.20 60.80 39.35 60.65

s(29.65) + p2.36(70.11) s(33.06) + p2.02(66.88) s(34.35) + p1.91(65.54) s(41.60) + p1.39(58.02) s(0.00) + p1.00(99.80) s(0.00) + p1.00(99.67) s(31.22) + p2.20(68.68) s(42.43) + p1.35(57.23) s(0.00) + p1.00(99.87) s(0.00) + p1.00(99.67) s(31.20) + p2.20(68.70) s(42.43) + p1.35(57.22) s(0.00) + p1.00(99.87) s(0.00) + p1.00(99.67) s(30.97) + p2.23(68.98) s(35.78) + p1.79(64.04) s(31.17) + p2.21(68.76) s(35.99) + p1.77(63.83) s(0.00) + p1.00(99.92) s(0.00) + p1.00(99.76) s(30.74) + p2.25(69.21) s(36.48) + p1.74(63.36) s(0.00) + p1.00(99.94) s(0.00) + p1.00(99.80) s(30.07) + p2.32(69.86) s(36.24) + p1.75(63.59)

Mulliken charge and natural atomic charge distribution Mulliken and natural atomic charge distribution of atoms in cocrystals 1 and 2 are given in Supporting information (vide Supporting information, Tables s-3 and s-4). As can be seen from Tables s-3 and s-4, the positive charges on hydrogen (H5 for 2-naa and H2 for 2-fpaa) bound to the O-atoms of 2-naa (O5) and 2-fpaa (O2) are found to be much higher than those for other H-atoms in 2-naa and 2-fpaa. This shows that these acidic

Bond orbital

Occupancy

Atoms

Contribution from parent NBO (%)

Atomic hybrid contributions (%)

Phendione C2AN1

1.98585

C2AN1

1.69657

C12AN1

1.98312

C5AO1

1.99559

C5AO1

1.95317

C11AN10

1.98312

C6AO2

1.99559

C6AO2

1.95317

C9AN10

1.98585

C9AN10

1.69657

C2 N1 C2 N1 C12 N1 C5 O1 C5 O1 C11 N10 C6 O2 C6 O2 C9 N10 C9 N10

40.43 59.57 41.08 58.92 58.15 41.85 34.41 65.59 35.46 64.54 41.85 58.15 34.41 65.59 35.46 64.54 59.57 40.43 58.92 41.08

s(31.35) + p2.19(68.58) s(35.56) + p1.81(64.24) s(0.00) + p1.00(99.93) s(0.00) + p1.00(99.74) s(35.72) + p1.79(64.09) s(31.08) + p2.22(68.87) s(31.14) + p2.21(68.75) s(42.43) + p1.35(57.23) s(0.00) + p1.00(99.87) s(0.00) + p1.00(99.67) s(31.08)p + 2.22(68.87) s(35.72) + p1.79(64.09) s(31.14) + p2.21(68.75) s(42.43) + p1.35(57.23) s(0.00) + p1.00(99.87) s(0.00) + p1.00(99.67) s(35.56) + p1.81(64.24) s(31.35) + p2.19(68.58) s(0.00) + p1.00(99.74) s(0.00) + p1.00(99.93)

C1 O1 O1 C11 C12 O3 C12 O3 C12 O2 O2 H2

32.20 67.80 66.81 33.19 34.14 65.86 32.45 67.55 31.15 68.85 74.95 25.05

s(24.44) + p3.08(75.35) s(32.73) + p2.05(67.20) s(28.95) + p2.45(70.99) s(22.11) + p3.51(77.66) s(34.44) + p1.90(65.45) s(42.40) + p1.35(57.20) s(0.00) + p1.00(99.82) s(0.00) + p1.00(99.64) s(27.66) + p2.61(72.07) s(33.64) + p1.97(66.29) s(21.67) + p3.61(78.25) s(99.78) + p0.00(0.22)

C8 O2 C8 O3 C8 O3 O2 H2

31.22 68.78 34.12 65.88 31.40 68.60 76.11 23.89

s(27.89) + p2.58(71.85) s(33.89) + p1.95(66.04) s(34.52) + p1.89(65.37) s(41.92) + p1.38(57.68) s(0.00) + p1.00(99.81) s(0.00) + p1.00(99.64) s(21.41) + p3.67(78.52) s(99.77) + p0.00(0.23)

2-naa C1AO1

1.98954

O1AC11

1.99003

C12AO3

1.99606

C12AO3

1.99169

C12AO2

1.99593

O2AH2

1.98507

2-fpaa C8AO2

1.99603

C8AO3

1.99812

C8AO3

1.99255

O2AH2

1.98613

protons (H5 and H2) have a tendency to accept electrons. In phendione, the strong negative charge is distributed on N-atoms, N1 and N2. This reveals that both N-atoms can act as electron donors. But in the cocrystals, one of the N-atoms (N2 for both 1 and 2) has a higher negative value than the other N-atom (N1 for both 1 and 2) in the phendione moiety. This confirmed that the hydrogen bonding is formed between the N-atom (N2 for both 1 and 2) of phendione moiety and acidic H-atom of 2-naa (H5) or 2-fpaa (H2) moiety.

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Natural bond orbital (NBO) analysis It is well-known that NBO analysis provides an efficient method for studying intra- and inter-molecular bonding and interactions among bonds and also provides a convenient basis for investigating charge transfer or conjugative interaction in molecular systems [32]. Delocalization of electron density between occupied Lewis type (bonded or lone pair) NBO orbitals and formally unoccupied (antibonded or Rydgberg) non-Lewis NBO orbitals correspond to a stabilizing donor–acceptor interaction (Table 6). BD(1) C10AN2 orbital with 1.98603 electrons has 39.38% C10 character in an sp2.32 hybrid and 60.62% N2 character in an sp1.76 hybrid. The sp2.32 hybrid on C-atom has 69.86% p-character and the sp1.76 hybrid on N-atom has 63.60% p-character in cocrystal 1. BD(1) O5AH5 orbital with 1.98454 electrons has 79.45% O5 character in an sp2.62 hybrid and 20.55% H5 character in an sp0.00 hybrid. The sp2.62 hybrid on O-atom has 72.32% p-character and the sp0.00 hybrid on H-atom has 0.27% p-character in cocrystal 1. The selected CAN (phendione) and OAH (2-naa/2-fpaa) bond orbital, sp character, and occupancy values are slightly changed in cocrystals 1 and 2. These results also indicate that the hydrogen bonding is formed between N-atom of phendione moiety and H-atom of 2-naa or 2-fpaa moiety. In order to investigate the intermolecular interactions, the stabilization energies of cocrystals 1 and 2 were computed using second-order perturbation theory. For each donor NBO(i) and acceptor NBO(j), the stabilization energy E(2) associated with electron delocalization between donor and acceptor is estimated [33,34] as, 2

Eð2Þ ¼ DEij ¼ qi

Fði; jÞ ej  ei

where qi is the donor orbital occupancy, ei and ej are diagonal elements (orbital energies), and F(i, j) is the off-diagonal NBO Fock Matrix element. The results of second-order perturbation theory analysis of the Fock Matrix at the B3LYP/6-31G(d,p) level of theory are presented in Table 7. The most important interaction energy in cocrystal 1 is electron donation from N2 LP(1) to the antibonding (O5AH5) resulting in a

stabilization energy of 22.84 kJ/mol, whereas in cocrystal 2, the electron donation from N2 LP(1) to O2AH2 results in a stabilization energy of 33.14 kJ/mol. The larger the E(2) value, the more intensive is the interaction between electron donors and electron acceptors and greater the extent of conjugation of the whole system. Therefore, we conclude from the NBO analysis that the H-bond is formed strongly between N-atom of phendione and H-atom of 2-naa in cocrystal 2. Conclusion Two new cocrystals, [(phendione)(2-naa)] (1) and [(phendione)(2-fpaa)] (2) have been synthesized using solvent mediated crystallization as well as neat grinding method. The single crystal X-ray diffraction data collection and refinement explored the complete molecular structure of the cocrystals stabilized through the hydrogen bonding. The OAH  N bond length of cocrystal 2 is lower than that of cocrystal 1 which shows cocrystal 2 is more stable than cocrystal 1. TGA results showed that cocrystals 1 and 2 were stabilized up to 210 °C. Binding energy, MEP, Mulliken charge, natural charge distribution, and NBO analysis confirmed the formation of intermolecular interactions in cocrystals 1 and 2, and the stability of cocrystal 2 is higher than that of the cocrystal 1. Dipole moment of cocrystal 2 is higher than those of its formers and hence cocrystal 2 is more polar and soluble in polar solvents. Acknowledgements One of the authors (G.S. Suresh Kumar) gratefully thanks CDRI, Lucknow, India for spectral studies. Authors thank Dr. K. Veluraja, Department of Physics, Manonmaniam Sundaranar University, Tirunelveli, Tamilnadu, India for PXRD data. Appendix A. Supplementary material CCDC 899820 and 899821 contain the supplementary crystallographic data for [(pnendione)(2-naa)] (1) and [(phendione) (2-fpaa)] (2) respectively. This can be obtained free of charge from

Table 7 Second order perturbation theory analysis of Fock Matrix of cocrystals 1 and 2 from NBO analysis using B3LYP/6-31G(d,p) method. Donor (i)–acceptor (j) interaction

Cocrystal 1

Donor (i)–acceptor (j) interaction

E(2)a (kJ mol1)

E(j)–E(i)b (a.u.)

F(i, j)c (a.u.)

1,10-Phenanthroline-5,6-dione LP(1)N1 ? p⁄(C3AC4) LP(1)N2 ? p⁄(C5AC6) LP(1)O1 ? RY⁄(1)C1 LP(1)O1 ? p⁄(C1AC2) LP(1)O1 ? p⁄(C1AC6) LP(1)O2 ? RY⁄(1)(C2) LP(1)O2 ? p⁄(C1AC2) LP(1)O2 ? p⁄(C2AC3)

10.54 9.63 14.30 23.85 19.48 14.30 23.88 19.45

0.89 0.90 1.55 0.62 0.71 1.55 0.62 0.71

0.088 0.085 0.133 0.109 0.106 0.133 0.109 0.106

2-Naphthoxyacetic acid LP(2)O3 ? p⁄(C13AC14) LP(1)O4 ? RY⁄(1)C24 LP(1)O4 ? r⁄(C24AC23) LP(1)O4 ? p⁄(C24AO4) LP(2)O5 ? p⁄(C24AO5)

31.54 14.67 22.04 28.80 57.56

0.35 1.43 0.62 0.66 0.32

0.097 0.130 0.107 0.125 0.123

0.80

0.122

1,10-Phenanthroline-5,6-dione to 2-naphthoxyacetic acid LP(1)N2 ? p⁄(O5AH5) 22.84

ED – Electron density. LP – Lone pair. RY – Rydberg. a E(2) – Energy of hyper conjugative interactions. b Energy difference between donor and acceptor i and j NBO orbitals. c F(i, j) – Fock Matrix element between i and j NBO orbitals.

Cocrystal 2 E(2)a (kJ mol1)

E(j)–E(i)b (a.u.)

F(i, j)c (a.u.)

1,10-Phenanthroline-5,6-dione LP(1)N1 ? p⁄(C28AC29) LP(1)N2 ? p⁄(C32AC33) LP(1)O5 ? RY⁄(1)C15 LP(1)O5 ? p⁄(C15AC16) LP(1)O5 ? p⁄(C15AC13) LP(1)O6 ? RY⁄(1)(C16) LP(1)O6 ? p⁄(C16AC17) LP(1)O6 ? p⁄(C16AC17)

10.52 9.58 14.30 23.88 19.48 14.30 23.85 19.52

0.89 0.90 1.55 0.62 0.71 1.55 0.62 0.71

0.087 0.085 0.133 0.109 0.106 0.133 0.109 0.106

2-Formylphenoxyacetic acid LP(1)O2 ? LP⁄(1)H2 LP(3)O2 ? RY⁄(1)H2 LP⁄(1)H2 ? RY⁄(1)H2 LP(1)N2 ? LP⁄(1)H2

13.66 18.62 29.19 33.14

0.71 1.71 1.05 0.53

0.099 0.178 0.324 0.130

1,10-Phenanthroline-5,6-dione to 2-formylphenoxyacetic acid LP(1)N2 ? p⁄(O2AH2) 33.14 0.53

0.130

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the Director, CCDC, 12, Union Road, Cambridge CBZ 1E2, UK. Email: [email protected]. Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.saa.2014.05.020.

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